HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 42, 35337-35345, October 21, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/42/35337    most recent M506460200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clarke, C. A. L. Articles by Clarke, P. R. Search for Related Content PubMed PubMed Citation Articles by Clarke, C. A. L. Articles by Clarke, P. R. Social Bookmarking                      What's this?

Cleavage of Claspin by Caspase-7 during Apoptosis Inhibits the Chk1 Pathway^*

From the Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom

Claspin is required for the phosphorylation and activation of the Chk1 protein kinase by ATR during DNA replication and in response to DNA damage. This checkpoint pathway plays a critical role in the resistance of cells to genotoxic stress. Here, we show that human Claspin is cleaved by caspase-7 during the initiation of apoptosis. In cells, induction of DNA damage by etoposide at first produced rapid phosphorylation of Chk1 at a site targeted by ATR. Subsequently, etoposide caused activation of caspase-7, cleavage of Claspin, and dephosphorylation of Chk1. In apoptotic cell extracts, Claspin was cleaved by caspase-7 at a single aspartate residue into a large N-terminal fragment and a smaller C-terminal fragment that contain different functional domains. The large N-terminal fragment was heavily phosphorylated in a human cell-free system in response to double-stranded DNA oligonucleotides, and this fragment retained Chk1 binding activity. In contrast, the smaller C-terminal fragment did not bind Chk1, but did associate with DNA and inhibited the DNA-dependent phosphorylation of Chk1 associated with its activation. These results indicate that cleavage of Claspin by caspase-7 inactivates the Chk1 signaling pathway. This mechanism may regulate the balance between cell cycle arrest and induction of apoptosis during the response to genotoxic stress.

Received for publication, June 14, 2005 , and in revised form, July 28, 2005.

^* This work was supported in part by a Cancer Research UK studentship (to C. A. L. C.) and senior research fellowship (to P. R. C.) and by a Biotechnology and Biological Sciences Committee studentship (to L. N. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK.

² To whom correspondence should be addressed: Biomedical Research Centre, Level 5, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK. Tel.: 44-1382-425580; Fax: 44-1382-669993; E-mail: paul.clarke{at}cancer.org.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Matsuura, M. Wakasugi, K. Yamashita, and T. Matsunaga Cleavage-mediated Activation of Chk1 during Apoptosis J. Biol. Chem., September 12, 2008; 283(37): 25485 - 25491. [Abstract] [Full Text] [PDF]

				L. Verlinden, I. Vanden Bempt, G. Eelen, M. Drijkoningen, I. Verlinden, K. Marchal, C. De Wolf-Peeters, M.-R. Christiaens, L. Michiels, R. Bouillon, et al. The E2F-Regulated Gene Chk1 Is Highly Expressed in Triple-Negative Estrogen Receptor /Progesterone Receptor /HER-2 Breast Carcinomas Cancer Res., July 15, 2007; 67(14): 6574 - 6581. [Abstract] [Full Text] [PDF]

				A. J. Faragher, X.-M. Sun, M. Butterworth, N. Harper, M. Mulheran, S. Ruchaud, W. C. Earnshaw, and G. M. Cohen Death Receptor-induced Apoptosis Reveals a Novel Interplay between the Chromosomal Passenger Complex and CENP-C during Interphase Mol. Biol. Cell, April 1, 2007; 18(4): 1337 - 1347. [Abstract] [Full Text] [PDF]

				H. Ishii, K. Mimori, H. Inoue, T. Inageta, K. Ishikawa, S. Semba, T. Druck, F. Trapasso, K. Tani, A. Vecchione, et al. Fhit Modulates the DNA Damage Checkpoint Response Cancer Res., December 1, 2006; 66(23): 11287 - 11292. [Abstract] [Full Text] [PDF]